1-224114325-G-C

Variant names:

• chr1-224114325-G-C
• NM_015176.4:c.196G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_015176.4(FBXO28):​c.196G>C​(p.Ala66Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBXO28 NM_015176.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.40
• Publications: 0 publications found

Genes affected

FBXO28 (HGNC:29046): (F-box protein 28) Members of the F-box protein family, such as FBXO28, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

FBXO28 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy 100

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-224114325-G-C is Pathogenic according to our data. Variant chr1-224114325-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3383319.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32470608). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015176.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO28	NM_015176.4	MANE Select	c.196G>C	p.Ala66Pro	missense	Exon 1 of 5	NP_055991.1	Q9NVF7-1
	FBXO28	NM_001136115.3		c.196G>C	p.Ala66Pro	missense	Exon 1 of 4	NP_001129587.1	Q9NVF7-2
	FBXO28	NR_049764.2		n.215G>C		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO28	ENST00000366862.10	TSL:1 MANE Select	c.196G>C	p.Ala66Pro	missense	Exon 1 of 5	ENSP00000355827.5	Q9NVF7-1
	FBXO28	ENST00000424254.6	TSL:1	c.196G>C	p.Ala66Pro	missense	Exon 1 of 4	ENSP00000416888.2	Q9NVF7-2
	FBXO28	ENST00000483773.1	TSL:2	n.155G>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy 100 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		8.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.23
Sift	Benign	0.12	T
Sift4G	Benign	0.19	T
Polyphen		0.96	P
Vest4		0.51
MutPred		0.50		Loss of sheet (P = 0.0181)
MVP		0.15
MPC		1.8
ClinPred		0.86	D
GERP RS		5.0
PromoterAI		0.025	Neutral
Varity_R		0.30
gMVP		0.58
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr1-224302027;